title: Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α.
abstract: Tumour necrosis factor-α (TNF) can activate NF-κB to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-κB pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.
authors.affiliation: Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Bingwei
authors.initials: B
authors.lastname: Wang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Tang
authors.forename: Jakub
authors.initials: J
authors.lastname: Siednienko
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*
chemical_list: D020690:GTPase-Activating Proteins; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; C584081:PELI3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8